While the prevalence of multi-drug resistant pathogens continues to rise, the rate at which new clinical antimicrobials are introduced has declined significantly. In addition, the treatment of persistent infections has been complicated by pathogen phenotypes. Bacteria that grow very slowly are often associated with prolonged infections, and they are particularly tolerant to many of the clinically important classes of antibiotics that inhibit rapidly growing cells. For example, the β-lactam family of antibiotics inhibits enzymes involved in the synthesis of peptidoglycan, and is thus most effective at targeting microbes that grow rapidly and continuously synthesize new cell wall. Relying on antibiotics that require fast metabolism and growth creates long-term problems, because dormant bacteria, as well as those associated with biofilms and other multicellular structures, may survive antibiotic treatments, become predisposed to developing drug resistance, and cause a relapse.
Previously, an assay was developed to detect specific inhibitors of chromosome portioning in Escherichia coli. (Oyamada et al., “Anucleate Cell Blue Assay: A Useful Tool for Identifying Novel Type II Topoisomerase Inhibitors,” Antimicrobial Agents and Chemotherapy, 50, pp. 348-350, (2006)). In the so-called anucleate cell blue assay, detection of anucleate cell production is used to screen for specific inhibitors of chromosome portioning. Compounds that inhibit either DNA gyrase or topoisomerase IV in vitro were identified and the antibacterial activity against certain drug-resistant Staphylococcus aureus strains was measured. The anucleate cell blue assay thus appears to be a useful tool for identifying potential antibiotics.
What are needed are new broad-spectrum antimicrobial compounds, particularly antimicrobial compounds that inhibit chromosome segregation during cell division and/or inhibit proteins responsible for maintaining the structure of the chromosome.